Meibomian glands are glands arranged vertically within the eyelid near the lashes. The force of an eyelid blink causes oil to be excreted onto the posterior lid margin. The oil is the “staying power” of the tears that helps prevent rapid tear evaporation. In a patient with Meibomian gland dysfunction (MGD), vision is affected because there is too much or too little oil in the tear film.
The meibomian glands are large sebaceous glands located in the eyelids, and unlike skin, are unassociated with hair. The meibomian glands produce the lipid layer of the tear film that protects it against evaporation of the aqueous phase. The meibomian gland orifice is located on the epithelial side of the lid margin, and is only a few hundred microns from the mucosal side. The glands are located on both upper and lower eyelids, with higher amounts of the glands on the upper eyelid. A single meibomian gland is composed of clusters of secretory acini that are arranged circularly around a long central duct and connected to it by short ductules. The terminal part of the central duct is lined by an ingrowth of the epidermis that covers the free lid margin and forms a short excretory duct that opens as an orifice at the posterior part of the lid margin just anterior to the mucocutaneous junction near the inner lid border. The oily secretion composed of lipids is synthesized within the secretory acini. The lipid secretion is a liquid at near body temperature and is delivered to the skin of the lid margin as a clear fluid, called “meibum.” It forms shallow reservoirs on the upper and lower lid margins, and consists of a complex mixture of cholesterol, wax, cholesteryl esters, phospholipids, with small amounts of triglycerides, triacylglycerols, and hydrocarbons. The separate meibomian glands are arranged in parallel, and in a single row throughout the length of the tarsal plates in the upper and lower lids. The extent of the glands corresponds roughly to the dimensions of the tarsal plates.
The eyelid margin is the source of physiologically important lipid secretion, meibum. The eyelid meibomian gland secretions form the outer layer of the tear film. Functions which have been attributed to this tear film lipid layer are: (1) a lubricant facilitating the movement of the eyelids during a blink, (2) a barrier preventing evaporation of the aqueous tear fluid, and (3) a barrier to the entry of microorganisms and organic matter such as pollen.
The moving eyelids spread meibum across the ocular surface and mix it with aqueous tears (AT), which are produced by lacrimal glands. Mixing and spreading of meibum and AT result in a near-continuous structure called tear film (TF), which covers the entire ocular surface and serves multiple purposes, including protective, lubricatory, nutritional, and antimicrobial, among others. TF was also linked to visual acuity because it provides a smoother ocular surface which improves the optical properties of the eye. However, TF is not homogeneous, which is not surprising considering that lipids do not easily form aqueous solutions and tend to separate by forming a clearly hydrophobic lipid-enriched sub-phase. A classical view on the TF structure presumes a three-layer organization of TF. As lipids are, typically, less dense than water, they accumulate on the surface of the aqueous sub-phase thus forming a lipid-enriched outer-most layer of TF (also called tear film lipid layer, or TFLL). Beneath the TFLL is a much more hydrophilic aqueous layer enriched with water-soluble proteins, carbohydrates, salts, and other more or less hydrophilic compounds. The closest to the corneal epithelium is believed to be a relatively hydrophilic mucin-enriched glycocalyx layer, which is formed primarily of membrane-bound mucins. By using interferometry, the depth of TFLL was estimated to be ˜40-90 nanometers, while the aqueous layer was found to be much thicker at about 4 micrometers. It is important to realize that all three layers are soft and dynamic structures, where changes occur as a result of numerous simultaneously manifesting factors, e.g. mechanical movements of the eyelids, continuous secretion of meibum, aqueous tears and mucins, and AT evaporation and drainage through nasal ducts. If the eye is forced to stay open without blinking, the human TF quickly deteriorates, thins, and breaks—a phenomenon known as tear break-up.
The tear break-up time (TBUT) for humans is measured in seconds. It has long been considered an important and objective diagnostic parameter in evaluating the health of the ocular surface. TBUT is widely used in ophthalmic practice to diagnose dry eye—a multifactorial condition (or disease) whose onset and progress is linked to the deterioration of TF in general, and TFLL in particular. When the break-up occurs, the cornea becomes exposed to air, causing a discomfort to the patient. The incomplete coverage of the ocular surface with TF also increases the chances of damage to the corneal epithelium cells because of excessive dehydration, abrasions, irritation, inflammation, infections, etc. Another cause of the TF instability are meibomian glands incapable of secreting enough meibum of the necessary quality, e.g. because of MGD associated with meibomian gland inflammation and/or obstruction.
Lipids produced by the meibomian glands are the main component of the superficial lipid layer of the tear film that protects it against evaporation of the aqueous phase and is believed also to stabilize the tear film by lowering surface tension. Alterations of the lipid phase more frequently point to MGD than alterations in isolated aqueous phase, as reported in a study by Heiligenhaus et al. (Heiligenhaus et al., Therapie. von Benetzungsstörungen. Klin. Monatsbl. Augenheilkd., 1994, Vol. 204, pages 162-168) where it was observed that a lipid deficiency occurred in 76.7% of dry eye patients compared with only 11.1% of those with isolated alterations of the aqueous phase. Hence, meibum lipids are essential for the maintenance of ocular surface health and integrity.
Lipids are the major components of meibum (also known as “meibomian gland secretions”). The biochemical composition of meibum is extremely complex and very different from that of sebum. Lipids are universally recognized as major components of human and animal meibum. In humans, more than 90 different proteins have been identified in meibomian gland secretions. A large number of investigators have attempted to characterize the meibum, and there has been a large range of amounts of lipids recovered by investigators (Table 1), the likely cause being the use of different collection and analysis techniques.
TABLE 1Type and Amount of Each Lipid Present in the Meibum.LipidPolarityAmountFree Fatty AcidsNon-Polar0.0-10.4%Wax EstersNon-Polar28.0-68.0% Cholesterol EstersNon-Polar0.0-39.0%DiestersNon-Polar2.3-17.6%Free sterolsNon-PolarTrace-30.0% MonoglyceridesNon-PolarTrace-2.6%DiglyceridesNon-PolarTrace-3.3%TriglyceridesNon-PolarTrace-9.0%Fatty Acid AmidesNon-PolarUnknownHydrocarbonsNon-PolarTrace-7.5%PhospholipidsPolar0.0-14.8%SphingolipidsPolarUnknownω-Hydroxy Fatty AcidsPolarUnknown
In subjects without MGD, the meibum lipid is a pool of clear oil. In MGD, the quantity, quality and composition of the secreted material is altered. Thus, MGD is characterized by lipid deficiency. Further, in MGD, the quality of expressed lipid varies in appearance from a clear fluid, to a viscous fluid containing particulate matter and densely opaque, toothpaste-like material. The meibomian orifices may exhibit elevations above surface level of the lid, which is referred to as plugging or pouting, and is due to obstruction of the terminal ducts and extrusion of a meibum lipids of increased viscosity.
Lipid deficiency and increased viscosity of meibum are important pathogenic factors in MGD and are observed in majority of cases of obstructive MGD. Therefore it is highly desired to enhance lipogenesis and lipid secretion from the meibomian gland, to overcome lipid deficiency as well as reduce the viscosity of meibum oil composition which allows for dissolution of any obstruction of the meibomian gland.
Highly viscous meibum is mixed with hyperkeratotic cell material, as seen in expressed pathologic human meibum prepared as smears or in impression cytology and in histopathology, as verified by molecular biology and immunohistochemistry. Increased viscosity has also been observed inside the obstructed glands of animal models. It is therefore desirable to soften and liquefy the obstructing lipids in order to open the duct and restore normal flow of excreted lipids.
Meibomian gland dysfunction, or MGD, is a leading contributor of dry eye syndrome, and is often characterized by insufficient lipid delivery, by the meibomian gland, to the surface of the eye. MGD, also termed posterior blepharitis, is the most common form of lid margin disease. In the early stages, patients are often asymptomatic, but if left unmanaged, MGD can cause or exacerbate dry eye symptoms and eyelid inflammation. The oil glands become blocked with thickened secretions. Chronically clogged glands eventually become unable to secrete oil which results in permanent changes in the tear film and dry eyes. Symptoms of MGD include eye dryness, burning sensation, itching, stickiness, watering, sensitivity to light, red eyes, and blurred vision.
MGD is a leading contributor of dry eye syndrome. The occurrence of dry eye syndrome is widespread and affects about 20 million patients in the United States alone. Dry eye syndrome is a disorder of the ocular surface resulting from either inadequate tear production or excessive evaporation of moisture from the surface of the eye. Tears are important to corneal health because the cornea does not contain blood vessels, and relies on tears to supply oxygen and nutrients. Tears and the tear film are composed of lipids, water, and mucus, and disruption of any of these can cause dry eye. MGD is not synonymous with posterior blepharitis, which describes inflammatory conditions of the posterior lid margin. MGD may cause posterior blepharitis, but MGD may not always be associated with inflammation or posterior blepharitis. Clinical signs of MGD include meibomian gland dropout, altered meibomian gland secretion, and changes in lid morphology.
Obstructive MGD is characterized by all or some of the following: 1) chronic ocular discomfort, 2) anatomic abnormalities around the meibomian gland orifice (which is one or more of the following: vascular engorgement, anterior or posterior displacement of the mucocutaneous junction, irregularity of the lid margin) and 3) obstruction or qualitative or quantitative changes in the glandular secretion (decreased meibum expression by moderate digital pressure).
Currently, standard treatment to MGD is somewhat limited to heating the lids to increase oil production and melt the oil that has solidified in the glands by warm compresses, applying light pressure to the lid margin near the lash line, and manually removing the thickened secretions as well as pharmacological treatments like antibiotics and anti-inflammatory agents. However, these treatments may be frustrating to patients and ophthalmologists. Massage of the eyelid provides only partial and temporary relief of obstruction of the meibomian glands and this could be painful. Conventional approaches for warm compresses apply heat to the outer surface of the eyelid; therefore the heat is frequently of limited effectiveness. The use of topical antibiotics and corticosteroids to suppress the bacterial colonization and inflammation of the eyelid margin associated with MGD has been shown to be effective in the relief of symptoms and the signs of MGD, however, the success of this treatment may have nothing to do with the changed meibum. Antibiotics, particularly the tetracyclines (including doxycycline, tetracycline, and minocycline) and azithromycin are used to suppress bacterial colonization and reduce inflammation of the lid margin; however, drug intolerance and prolonged therapy have limited the clinical application of oral antibiotics.
Lid hygiene is considered the primary treatment for MGD and consists of three components: 1) application of heat, 2) mechanical massage of eyelids and 3) cleansing the eyelid. Eyelid warming procedures improve meibomian gland secretion by melting the pathologically altered meibomian lipids. Warming is achieved by warm compresses or devices. Mechanical lid hygiene includes the use of scrubs, mechanical expression and cleansing with various solutions of the eyelashes and lid margins. Lid margins are optionally also cleansed with hypoallergenic bar soap, dilute infant shampoo or commercial lid scrubs. Physical expression of meibomian glands is performed in a physician's office or is performed by the patient at home. The technique varies from gentle massage of the lids against the eyeball to forceful squeezing of the lids either against each other or between a rigid object on the inner lid surface and a finger, thumb, or rigid object (such as a glass rod, Q-tip, or metal paddle) on the outer lid surface. The rigid object on the inner lid surface protects the eyeball from forces transferred through the eyelid during expression and to offer a stable resistance, to increase the amount of force that is applied to the glands.
Eyelid warming is limited because the warming melts the lipids, but does not address movement of the keratinized material. Further, eyelid warming induces transient visual degradation due to corneal distortion. Mechanical lid hygiene is also limited because the force needed to remove an obstruction can be significant, resulting in significant pain to the patient. The effectiveness of mechanical lid hygiene is limited by the patient's ability to tolerate the associated pain during the procedure. Other treatments for MGD are limited.
Physical opening of meibomian glands obstruction by meibomian gland expression is an acceptable method to improve meibomian gland secretion and dry eye symptoms. In addition probing of the meibomian gland canal has been used to open the obstructed canal. Both methods, expression and probing, are limited, however, by the pain induced by the procedure, the possible physical insult to the gland and canal structures and their short lived effect estimated at days and weeks.
In summary, each of these treatments has a different shortcoming and the treatment of MGD remains challenging. Therefore, methods are needed to improve patient comfort, which will not cause harm to the meibomian glands and canals, that will reduce the dependency on frequent office visits and improve secretion of meibum.
Emerging treatments for MGD include the use of mucolytic and/or keratolytic agents. The goal of mucolytic therapy is to facilitate physiological clearance by optimizing the viscoelasticity of mucus, while keratolytic therapy aims to soften keratin, a major component of the skin.
Acetylcysteine, also known as N-acetylcysteine or N-acetyl-L-cysteine (abbreviated NAC), is a pharmaceutical drug and nutritional supplement used primarily as a mucolytic agent. Acetylcysteine is an acetylated derivative of L-cysteine where an acetyl group is attached to the nitrogen atom, known to have mucolytic, anti-collagenolytic, and anti-oxidant properties. It is used as a cough medicine since it breaks disulfide bonds in mucus and liquefies it, making it easier to cough up. It is also this action of breaking disulfide bonds that makes it useful in thinning the abnormally thick mucus in cystic and pulmonary fibrosis patients. Akyol-Salman et al., (J. Ocul. Pharmacol. Ther., 2010, Vol. 26(4), pages 329-33) evaluated the efficacy of topical N-acetyl-cysteine (NAC) therapy in patients with meibomian gland dysfunction (MGD). Qiao and Yan (Clinical Ophthalmology 2013, Vol. 7, pages 1797-1803) reviewed several emerging treatment options for MGD, including NAC.
Despite the possible treatment options for MGD, it is still difficult to obtain complete relief of signs and symptoms.